All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Malignant gliomas are the most common (60-70%) of all CNS/brain tumors. Annually there are approximately 5 cases of malignant gliomas per 100,000 people and over 14,000 new cases are diagnosed each year in the United States (1, 2). Surgery remains the standard therapy for primary brain tumors. Although surgery may be combined with radiation therapy and/or followed with chemotherapy to destroy remaining cancer cells, patients still have a poor survival advantage (3-5). In recent years, the prodrug Temozolomide (TMZ, TEMODAR), for example, which undergoes spontaneous conversion to the active alkylating agent, has emerged as a potent chemotherapeutic agent (6). In combination with radiotherapy, it has been shown to substantially increase median survival compared with radiotherapy alone (7). However, as with many potential chemotherapeutic agents, TMZ has considerable toxicity, which prevents therapeutic dosage increase. Moreover, another limiting factor of TMZ treatment is tumor resistance to the drug (8-10).
Thus, there is a need in the art for novel drug delivery systems that have tumor targeting, increased solubility, enhanced accumulation in solid tumors, decreased general toxicity, increased maximum tolerated doses, circumvention of multidrug resistance and enhanced apoptosis induction.